Each year, more than 700,000 US adults elect total joint replacement (TJR) surgery to restore physical function and eliminate the pain of advanced knee or hip arthritis that persists despite comprehensive medical treatment. Despite broad use, wide variation persists in surgical practice and outcomes. Furthermore, there is a lack of comparative effectiveness data to guide surgeon and patient decisions on optimal implant timing, surgical approach, implant selection, and peri-operative management to prevent adverse sequelae and revision. Therefore, the National Orthopedic Outcome Registry (NOOR) and Cohort Study will establish a national registry of over 33,000 diverse patients of 130 orthopedic surgeons representing all regions of the country and varied hospital and surgeon practice settings. As such, the registry is designed to reflect typical US clinical practice, rather than focusing exclusively on high-volume academic centers. Data will include baseline patient attributes; procedure approach and technology; hospital course; surgeon and institutional characteristics; longitudinal patient function, post-procedure complications and revisions, and serum/DNA samples. Web-based data collection will enhance efficient data gathering. The research team will develop new outcome measures and will determine the relative contributions of patient factors, technology use, and delivery factors to (1) early functional failure and (2) adverse post-arthroplasty events; (3) examine disparities in TJR use and outcome, seeking to elucidate root causes; and (4) conduct economic analyses to determine the personal and societal value of TJR in working aged adults. A national network of orthopedists will partner with innovative scientists with expertise in large-scale registry development and implementation, web-based technology, outcome measurement, and statistical techniques to assure success. Sound governance principles will ensure efficient implementation. The registry will actively encourage ancillary research to assure optimal use of all data and biomaterials. We propose to transform the network of clinical centers and orthopedic offices into a research laboratory that will serve as a national model for comparative effectiveness research.